Needleless Injector Drug Capsule and a Method for Filling Thereof

ABSTRACT

A method for filling needleless injector capsules with liquid drug, whereby dissolved gas within the drug is replaced by a less soluble gas in order to reduce the inclusion of gas bubbles, or to prevent the growth of bubbles during storage and thereby prevent breakage of the capsules.

BACKGROUND OF THE INVENTION

Needleless injectors are used as an alternative to needle-typehypodermic injectors for delivering liquid drugs and other substancesthrough the skin and into the underlying tissues. The drug is dispensedfrom a drug capsule having a piston which is driven with sufficientforce that the drug is expelled at sufficiently high pressure to piercethe skin. Typically, the drug capsule will comprise a hollow cylindricalchamber with a discharge orifice at one end, and a piston slidingly andsealingly located at the other. The piston is caused to move towards theorifice to dispense the drug by a ram, powered by a variety of meanssuch as a spring, pressurised gas or pyrotechnic charge. The orificediameter can vary from about 0.08 nm to about 0.7 mm, according to theapplication.

The more successful and controllable injectors employ a two-phaseinjection pressure profile; the first is a short but very high pressurepulse to puncture the skin and the second is at a lower pressure todispense the drug through the hole thus formed. Typically, the firstpressure pulse will be of around 100 microsecond duration, and have apeak pressure of 300-500 bar, and the second will last for around 200milliseconds with a pressure of around 100 bar. The duration of thesecond phase will vary according to the volume to be delivered.

It is highly preferred that the drug capsule is transparent, so that thecontents may be checked for accuracy and contamination. This requirementhas placed a severe limitation on the types of materials that may beused, because the transparent material must be strong enough towithstand the extremely high pressures, and must not adversely affectthe drug. As a consequence, virtually all of the needleless injectorsproposed use a plastic drug capsule, typically made from polycarbonate.However, such materials are generally unsuitable for storing the drug,because they absorb water from the drug, or are permeable to oxygen, orreact in some way with the drug. Therefore, drug capsules made fromplastics are required-to be filled immediately before use, a ratherinconvenient procedure, with risk of inaccurate filling andcontamination, and requiring training of the operators.

The only material with a long history of satisfactory drug storage isborosilicate glass, but this is very brittle and hence there have beenfew injectors with glass capsules. The obvious problem with glasscapsules is that particles of glass are ejected if they burst. Theunderlying causes of the weakness of glass capsules are tiny flaws whichoccur during manufacture, such as scratches, and cracks throughincorrect control of temperatures.

The “Intraject” manufactured by Weston Medical Limited is a pre-filledsingle-use disposable needleless injector, having one of the very fewglass capsules suitable for long term drug storage. This is aborosilicate drug capsule of up to 1 ml capacity, made to exceedinglyclose manufacturing specifications, and further improved by ion exchangestrengthening. The breakage rate for these capsules is exceptionallylow, but it is desirable to reduce this still further.

Several attempts have been made to reduce the breakage rate for thesecapsules. For example, further layers of material have been added to thecapsule to provide increased physical strength (see international patentpublication WO96/15821 in the name of Weston Medical Limited). However,this approach increases significantly the manufacturing costs of thecapsule. An alternative approach has been to reduce the number of flawsin the material of the drug capsule, particularly around the dischargeorifice. One method of doing this has been to manufacture the capsulewithout an orifice and then use a laser to drill precisely the orifice(see international patent publication WO01/58638 in the name of WestonMedical Limited). Despite these advances, there is still a requirementfor further reducing the incidence of breakages.

Summary of the Invention

Accordingly, the present invention provides a needleless injector drugcapsule containing a liquid drug wherein the liquid drug has been purgedby an inert gas having a low solubility in the liquid drug.

Surprisingly, it has been found that the presence of small bubbles ofgas previously in solution encourage breakages in the drug capsule andthat removal or reduction of these solute gases by purging with a gashaving a low solubility reduces the incidence of breakages.

The capsule is preferably made from borosilicate glass, and which mayhave undergone ion exchange strengthening.

Preferably the inert gas has a solubility of 0.5 to 25 cm³ in 100 cm³ ofthe liquid drug.

Preferably the inert gas is one or more of helium, argon, neon, krypton,xenon, nitrogen, one or more chlorofluorocarbons and/or one or morehydrofluorocarbons and particularly preferably helium.

In another embodiment of the invention, a needleless injector drugcapsule is provided containing a liquid drug wherein the liquid drug hasbeen purged by a gas having a substantially constant solubility in theliquid drug over a range of temperatures corresponding to the storagetemperatures for the liquid drug. This range of temperatures may be 0°C. to 30° C.

In another embodiment the present invention provides a method forfilling a needleless injector drug capsule with a liquid drug, themethod comprising purging the liquid drug with an inert gas having a lowsolubility in the liquid drug, and filling the capsule.

Preferably the purging process is carried out at a temperaturecorresponding to the lowest solubility of the inert gas in the liquiddrug.

Preferably the inert gas is helium and the purging process is thencarried out at 25° C. to 35° C.

Preferably, prior to contact with the liquid drug, the inert gas isforced through a filter having apertures of not more than 0.2 μm.

The liquid drug is preferably stirred during purging.

In another embodiment, the invention provides a method for filling aneedleless injector drug capsule with a liquid drug comprising purgingthe liquid drug with a gas having a substantially constant solubility inthe liquid drug over a range of temperatures corresponding to thestorage temperatures for the liquid drug.

BRIEF DESCRIPTION OF THE DRAWINGS

Example of the invention, will now be described in detail with referenceto the accompanying drawings, in which:

FIG. 1 shows the variation of the solubility of a number of gases inwater with temperature;

FIG. 2 shows in greater detail the variation of the solubility of heliumin water with temperature;

FIG. 3 shows the rate of increase of helium under five differentconditions for a sparging method of the invention using helium;

FIG. 4 shows the rate at which nitrogen and oxygen are displaced byhelium for the five different conditions of FIG. 4; and

FIG. 5 compares the rate of increase of helium with the rate of decreaseof nitrogen and oxygen.

DETAILED DESCRIPTION

Careful investigation of the causes of breakage of the drug capsule hasrevealed that, in addition to manufacturing flaws in the glass, bubblesof gas (normally air) entrained in the drug may result in the fractureof the capsule. The high initial pressure in the injection cycle causesbubble collapse resulting in localised high stress in the region of thedischarge orifice of the capsule (where the bubbles tend to collect).Filling under vacuum will practically eliminate the bubbles of airpresent in the liquid drug at the time of filling, but dissolved gastends to come out of solution during storage. Bubbles of up to 2 μlvolume do not appear to cause breakage, but above this, the incidence ofbreakage rises with increasing bubble size.

The present invention seeks to reduce the evolution of gas bubbles fromthe drug by replacing the dissolved gas by a gas of low solubility inthe liquid drug. Interestingly, the applicant has found that alternativemethods of removing dissolved gas, e.g. by applying a vacuum to theliquid or sonication of the liquid do not work for certain drug types.Applying a vacuum, for example, has the drawback of removing volatilecomponents which may be part of the drug, and water, in addition to thedissolved gas; This can result in an unacceptable change in the drugformulation. Sonication results in “hot-spots” in the liquid which canthermally degrade the drug.

The applicant has found that purging a liquid drug with an inert gas,such as helium (He), effectively displaces dissolved gases, particularlyoxygen and nitrogen, and that the drug may then be stored within a drugcapsule without the risk of gas bubbles appearing during storage atnormal temperatures.

Pre-treatment of the drug product by sparging with low solubility gasspecies minimises the total mass of dissolved gas. By selecting asparging gas with a low variation in solubility of the gas in the drugas a function of temperature, the propensity for those gases to come outof solution during temperature cycling is also minimised. Helium is onegas satisfying this condition.

Other gases may be used according to the application such as neon,argon, krypton or xenon. Other inert gases of low solubility may also beused, including nitrogen as well as chlorofluorocarbons andhydrofluorocarbons.

FIG. 1 shows the solubility of various gases in water over temperature.A flat solubility curve over a range of temperatures corresponding tothe temperature range expected during storage will prevent gas comingout of solution during storage.

Plots are shown in FIG. 1 for Hydrogen, Helium, Nitrogen, Oxygen, Neon,Argon, Krpton and Xenon. The storage temperature range may typically be280° K to 310° K, and a flat solubility curve over this range oftemperatures is desired, in addition to low solubility and an “inert”property of the gas. As shown, hydrogen, helium, neon and nitrogen bestsatisfy the solubility requirements.

The term “inert” used herein denotes a gas which will not react with theliquid drug at normal temperatures and pressures. The term “lowsolubility” denotes a solubility of the inert gas in the liquid drugwhich reduces the incidence of bubbles in the liquid drug. Preferablythe solubility is from 0.5 to 25 cm³ in 100 cm³ of the liquid drug,preferably 0.9 to 5.0 cm³ in 100 cm³ of the liquid drug and particularlypreferably from 0.9 to 1.5 cm³ in 100 cm³ of the liquid drug. Solubilityis measured at 25° C. The term “liquid drug” denotes a drug which isliquid at room temperature and pressure, or a drug dissolved orsuspended in a solvent, such as water.

A preferred embodiment of the invention is to “sparge” the liquid drugwith tiny bubbles of a sparging gas.

Taking helium as one specific example, FIG. 2 shows that the solubilityof helium is at its lowest at approximately 30° C., and wherever thedrug is stable at such temperature, it is particularly preferred toconduct the sparging process at this temperature, with a tolerance ofabout +/−5° C. Preferably, the bubbles may be generated by forcingpressurised helium through a sterile 0.2 micron filter placed in thebottom of a vessel. This produces a very large number of very smallbubbles, and after treating, say, 2 litres of an aqueous drug for 15minutes, the sparging device is removed, and the vessel sealed in ahelium (or other gas used for sparging) atmosphere, with minimalover-pressure, until required for the filling of injector capsules.

Obviously, the duration of the treatment will vary according to thevolume of liquid, the gas pressure, volume flow rate, and the size andnumber of the bubbles generated by the sparging device. The gas pressureand volume flow rate are of course linked. Preferably, capsule fillingis carried out by first evacuating the capsule to about 0.5 mbar beforeadmitting the drug into the capsule; a full description of a suitableprocess is disclosed in International patent publicationWO02/060516—“Method for filling needleless injection capsules” in thename of Weston Medical Limited.

It has also been found that stirring of the liquid during spargingreduces the required sparging time. In particular, it has been foundthat key input parameters for the control of the sparging process arestirring speed (for example using a magnetic mixer) and the gas flowrate. Increasing the gas flow rate reduces the tine required, but thereis a maximum practical gas flow rate above which foaming of the drugbeing sparged is too great. The additional step of stirring reducesfurther the time required by increasing the time taken for the sparginggas to travel through the liquid, for the same gas flow rate. In orderto monitor the rate at which gas is displaced by the sparging gas, anoxygen probe is used. The air being removed from the drug by sparging isof course almost entirely nitrogen and oxygen, and it has been foundthat the concentration of dissolved nitrogen and oxygen can be deducedfrom a measurement of the dissolved oxygen concentration alone.

In order to analyse the effects of the stirring rate and the gas flowrate, a number of experiments were carried out. The table below show theexperimental conditions for 5 tests, in which helium was used as thesparging gas. All conditions were equal other than the stirring speedand flow rate. The experiments involved the sparging of 3 litres ofsolution in a 5 litre Schott glass bottle, with an oxygen probe used tomeasure (and deduce) the dissolved gas concentrations. In theseexperiments, the solution contained 0.1% polysorbate 80.

Experiment number 1 2 3 4 5 6 7 Magnetic mixer speed 150 150 150 250 350250 250 (rpm) Fine flow meter 80 150 190 145 145 150 150 (ml · min⁻¹)

FIG. 3 shows the evolution over time of the helium concentration in thedrug. Using best fit techniques, the curves can be characterised asexponential graphs, each having a characteristic time constant, A

As there are two sets of three experiments where either the stirrerspeed or the flow rate is held constant, it is possible to explore thevariation of β as a function of each variable. In both cases, aproportional relationship is found. This suggests that the variables areindependent and proportional. From this, it is found that β varies twiceas much with stirring speed as with the gas flow rate, so that thestirrer speed is approximately twice as important as the gas flow rate.

FIG. 4 shows the concentration of oxygen and nitrogen over time for thefive experimental conditions. The decay curves also follow theexponential model and agree with the graphs of FIG. 3.

It is then possible to compare the time constants for the exponentialincrease in helium concentration and for the exponential decrease incombined nitrogen and oxygen concentration. FIG. 5 shows thiscomparison, with the five plotted point representing the fiveexperiments. There is clearly a proportional relationship between thetwo time constants for different sparging conditions. The constant ofproportionality is given as 0.575.

The principal conclusion is that the helium concentration varies atapproximately 1.75 times the speed of the combined nitrogen and oxygenconcentration. The helium mass transfer process is quicker than thenitrogen and oxygen processes. Selecting the optimum sparging conditionsresults in operation at the high gas transfer rate portion of the linein FIG. 5.

The sparging operation effectively displaces the dissolved gases in thedrug. By selecting the sparging gas to have a flat solubility curve overtemperature, the possibility of gas coming out of solution duringstorage is minimised. As a result, the capsule can be formed from amaterial which is impermeable to the sparging gas, as there is no needto discharge the sparging gas. For example, a borosilicate glass capsuleis selected partly for its impermeability to oxygen, which preventsdeterioration of the stored drug. Such a capsule is also impermeable tonitrogen. However, nitrogen can still be used as a sparging gas,particularly if the sparging conditions are selected to correspond tothe minimum solubility of nitrogen.

Thus, although examples are given for sparging conditions with helium,the invention is not restricted to helium, and other gases suitable forsparging have been identified.

As can be seen from the experiments above, a preferred stirring speed isin the range 100 rpm to 300 rpm, preferably 200 rpm to 300 rpm.

Other modifications will be apparent to those skilled in the art.

1. A needleless injector drug capsule containing a liquid drug whereinthe liquid drug has been purged by an inert gas having a low solubilityin the liquid drug.
 2. A needleless injector drug capsule as claimed inclaim 1, wherein the capsule is comprised of borosilicate glass.
 3. Aneedleless injector drug capsule as claimed in claim 2, wherein theborosilicate glass of the capsule has undergone ion exchangestrengthening.
 4. A needleless injector drug capsule as claimed in claim1, wherein the inert gas has a solubility of 0.5 cm³ to 25 cm³ in 100cm³ of the liquid drug.
 5. A needleless injector drug capsule as claimedin claim 1, wherein the inert gas is selected from the group consistingof helium, argon, neon, krypton, xenon, nitrogen, a chlorofluorocarbon,a hydrofluorocarbon, and a mixture thereof.
 6. (canceled)
 7. Aneedleless injector drug capsule as claimed in any one of claim claim 1,wherein the inert gas does not include helium.
 8. A needleless injectordrug capsule as claimed in claim 1, wherein the capsule is comprised ofglass strengthened by ion exchange and the capsule is filled with aliquid drug.
 9. A method for filling a needleless injector drug capsulewith a liquid drug comprising purging a liquid drug with an inert gashaving a low solubility in the liquid drug, and filling the capsule withpurged liquid drug.
 10. A method as claimed in claim 9, wherein fillingthe capsule comprises evacuating the capsule to about 0.5 mbar andadmitting the drug into the capsule.
 11. A method as claimed in claim 9,wherein the capsule is comprised of borosilicate glass.
 12. A method asclaimed in claim 11, wherein the borosilicate glass of the capsule hasundergone ion exchange strengthening.
 13. A method as claimed in claim12, wherein the liquid drug is purged in a vessel, the vessel beingsealed in an atmosphere of the purging gas before filling the capsulewith purged liquid drug.
 14. A method as claimed in claim 9, wherein theinert gas has a solubility of 0.5 cm³ to 25 cm³ in 100 cm³ of the liquiddrug.
 15. A method as claimed in claim 9, wherein the inert gas isselected from the group consisting of helium, argon, neon, krypton,xenon, nitrogen, a chlorofluorocarbon, a hydrofluorocarbons and amixture thereof.
 16. (canceled)
 17. A method as claimed in claim 9,wherein the inert gas does not include helium.
 18. A method of claim 15,wherein the inert gas is helium.
 19. A method as claimed in claim 14,wherein the purging process is carried out at a temperaturecorresponding to the lowest solubility of the inert gas in the liquiddrug.
 20. A method as claimed in claim 19 wherein the inert gas ishelium and the purging process is carried out at 25° C. to 35° C.
 21. Amethod as claimed in claim 19, wherein, prior to contact with the liquiddrug, the inert gas is forced through a filter having apertures of notmore than 0.1 mm.
 22. A method as claimed in claim 21 wherein, prior tocontact with the liquid drug, the inert gas is forced through a filterhaving apertures of not more than 0.2 μm.
 23. A method as claimed inclaim 9, further comprising: stirring the liquid during purging.
 24. Aneedleless injector drug capsule containing a liquid drug wherein theliquid drug has been purged by a gas having a substantially constantsolubility in the liquid drug over a range of temperatures correspondingto the storage temperatures for the liquid drug.
 25. A needlelessinjector capsule as claimed in claim 24, wherein the range oftemperatures is 0° C. to 30° C.
 26. A method for filling a needlelessinjector drug capsule with a liquid drug comprising purging the liquiddrug with a gas having a substantially constant solubility in the liquiddrug over a range of temperatures corresponding to the storagetemperatures for the liquid drug.